Human neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by adult onset, progressive neurologic dysfunction, and a paucity of effective therapies. These common disorders produce substantial disability, and their importance to public health is expected to increase as the population ages. One or more causative genes have now been isolated for familial forms of each of these four devastating neurologic illnesses, making possible the development of transgenic mouse models. Although such animal models now exist, the exact mechanisms by which mutant genes cause neurologic diseases remains unclear. Unless the etiologic mechanisms underlying neurodegenerative diseases are clearly identified,rational therapeutic interventions will be impossible. The neurotransmitter glutamate has been implicated as a causative factor in the etiology of neurodegenerative disorders. Specifically, one class of glutamate receptors, the metabotropic glutamate receptors (mGluRs), may be specifically abnormal in many of the neurodegenerative disorders. This project will examine metabotropic glutamate receptors in transgenic mouse models of AD, PD, HD, and ALS using ligand binding, in situ hybridization, immunohistochemstry, and Western blotting. Alteration of mGluR expression level is also predicted to have direct implications for the abnormal synaptic functioning which is characteristic of neurodegenerative diseases. Thus, we will also explore glutamate-related intracellular signaling pathways in the brains of transgenic mice. Finally, if mGluR dysfunction is an important part of disease etiology, drugs targeting mGluRs may ameliorate symptoms in certain of these models. We will test if administration of mGluR-active medications improves clinical outcome in mouse models of these diseases. PERFORMANCE blTE(S) (organization, city, state) Neurology Service Massachusetts General Hospital Fruit Street Boston, MA 02114 KEY PERSONNEL. See instructions on Page 11. Use continuation pages as needed to provide the required information in the format shown below. Name Organization Role on Project Anne B. Young, M.D.,Ph.D. Massachusetts General Hospital Principal Investigator L)J Jang-Ho Cha, M.D., Ph.D. Massachusetts General Hospital Investigator QJ David G. Standaert, M.D., Ph.D. Massachusetts General Hospital Investigator C l^Anthone Dunah, Ph.D. Massachusetts General Hospital Investigator ^-l/Zane R. Hollingsworth, M.P.H. Massachusetts General Hospital Investigator Lv LiannaR. Orlando, M.M.Sc.i^ ^ Massachusetts General Hospital Investigator Laurie Farrell,B.S. Massachusetts General Hospital Research Assistant Tara Razzano,B.S. Massachusetts General Hospital Research Assistant PHS 398 (Rev. 4/98) Page 2 BB Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. Young, Anne B. CC Principal^^tigator/Program Director (Last, first, middle):. Type the name of the principal investigator/program director at the top of each printed page and each continuation page. (For type specifications, see instructions on page 6.) RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,